Melanoma is a serious form of skin cancer often metastasizing to vital organs and other tissues and resulting in high morbidity and mortality. Melanoma is one of the most aggressive cancer types in humans. Melanoma accounts for only about 4% of skin cancers but for as many as 74% of all skin cancer deaths. The worldwide incidence of melanoma has increased over the past few decades, with more than 132,000 people diagnosed with the disease every year (World Health Organization). In the United States, nearly 9,500 individuals will die of melanoma in 2013 (Siegel et al., CA Cancer J. Clin., 2013, 63: 11-30). If melanoma is diagnosed early, it can be cured by surgical excision and this is what occurs in about 80% of the cases. However, metastatic melanoma is refractory to current therapies and has a poor prognosis with a median survival rate of 6 months.
The prognosis of melanoma is based on histopathological criteria described in the American Joint Committee on Cancer (AJCC) melanoma staging system. These include the Breslow index, mitotic rate, ulceration status and extent of lymph node involvement (Balch et al., J. Clin. Oncol., 2009, 27: 6199-6206). Despite this staging system, the clinical behavior of melanoma is often unpredictable (Nagore et al., Melanoma Res., 2005, 15: 169-177) because melanoma is a group of diseases with various biological subtypes (Lomas et al., Front Biosci., 2008, 13: 5071-5093). In addition, patients with melanoma metastatic to the skin show variable survival: some may survive a long time, whereas some die of disseminated disease within one year of removal of skin metastases (Hofmann-Wellenhof et al., J. Cutan. Pathol., 1996, 23: 199-204).
Studies based on melanoma gene expression profiling have been performed in order to improve the prognosis of the disease and to predict the response of patients to treatment (Hoek, Pigment Cell Res., 2007, 20: 466-484). First, a comparison of gene expression profiles of normal skin, nevi and primary and metastatic melanomas has identified 2602 signature genes that could be used to distinguish two metastatic patterns, which are already emergent in large melanoma primaries (Haqq et al., Proc. Natl. Acad. Sci. USA, 2005, 102: 6092-6097). Second, cDNA expression microarray in primary melanoma has revealed a signature of 254 genes characterizing patients at risk of developing distant metastases (Winnepenninckx et al., J. Natl. Cancer Inst., 2006, 98: 472-482). Third, high-throughput gene microarray in metastatic melanoma has determined a set of 80 probes (70 genes) associated with survival (Mandruzzato et al., J. Transl. Med., 2006, 4: 50). Finally, molecular profiling of lymph node metastases of stage III melanoma patients has disclosed 21 genes whose expression levels correlated with clinical outcome (John et al., Clin. Cancer, 2008, 14: 5173-5180). Thus, several new marker genes have shown promise, and large scale studies are now warranted to clinically validate them for the development of new prognostic tools, diagnostic approaches and biological-targeted therapies (Larson et al., Nat. Clin. Pract. Oncol., 2009, 6: 105-117).
Such gene discovery platforms may help to identify new molecular markers in melanoma metastases, enabling one to redefine the prognosis at the time of tumor progression, especially in thin melanomas. They may also help to establish a prognosis in patients with unknown melanoma primaries (2-6% of all melanoma cases) (Schlagenhauff et al., Cancer, 1997, 80: 60-65). The identification of such markers in high-risk melanoma patients would be important for designing and interpreting clinical trials and could be of great benefit as one might also foresee the development of useful and effective adjuvant therapies.
Thus, even though progress has been made in the field, there still remains, in the art, an ongoing need for new strategies for the treatment and/or management of metastatic melanoma, and for the development of prognostic tools.